A novel phospholipid gemcitabine conjugate is able to bypass three drug-resistance mechanisms

Abstract

We have previously synthesized a phospholipid-gemcitabine conjugate and a phospholipid-cytosine arabinoside conjugate that we tested in different human cancer cell lines. The gemcitabine conjugate was more cytotoxic to the cancer cells tested than the cytosine arabinoside (ara-C) conjugate. The focus here was to elucidate the mechanism of action of the conjugate molecule and its ability to bypass certain drug-resistance mechanisms. In contrast to gemcitabine, the gemcitabine conjugate did not enter the cell via the human equilibrative nucleoside transporter (hENT1). Additionally, the gemcitabine conjugate was not a substrate for the multidrug resistance efflux pump, MDR-1, even though the molecule is more lipophilic. Finally, we showed that deoxycytidine kinase (dCK) was not required for the activation of the gemcitabine conjugate. As expected, cells overexpressing dCK were more sensitive to gemcitabine whereas cells overexpressing dCK were not more sensitive to the gemcitabine conjugate. Taken together, these results suggest that the gemcitabine conjugate may be therapeutically superior to gemcitabine due to the conjugate's ability to bypass three resistance mechanisms that often render gemcitabine ineffective as an anticancer agent.

Preparation of albumin nanospheres loaded with gemcitabine and their cytotoxicity against BXPC-3 cells in vitro

“…An important feature of the method in this study was that the molecular structure of GEM remained unchanged, as compared with other GEM-loaded particledelivery systems, in which the particles were prepared with GEM precursors, derivatives, or other modified structures [36][37][38][39] . Although such changes might improve GEM loading or stability, and might even maintain the drug's cytotoxicity, these modified products introduced new chemical compounds, and their pharmacodynamics, pharmacokinetics, safety, and clinical effects must be re-evaluated.…”

“…However, since pure GEM is rapidly metabolized, prolongation of the release time of GEM by GEM-NSPs represents an improvement. The water solubility of GEM can be reduced by molecular modifica tion [18,19,[36][37][38][39] , such as modification with hydrophobic stearo-chains, aminoacids, or pteroylglutamic acid. Although these strategies would likely improve drug loading and slow release, the pharmacodynamic action of GEM derivates, ie, new molecules, would require an overall re-evaluation.…”

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

“…121,129 Conversely, ''free'' anthracycline following passive diffusion across the intact lipid bilayer of cell membranes is primarily detected complexed with nuclear DNA < 30 minutes after initial exposure 121 while anthracycline liberated from covalent anthracyclineimmunochemotherapeutics reportedly distributes to, and accumulates within the nucleus, mitochondria, and golgi compartments. 63 One of the primary objectives for the molecular design, synthesis, and evaluation of the cytotoxic potency of [i] 21,30,130,131 In doing so, mammary adenocarcinoma SKBr-3 is given an extended opportunity to continually internalize progressively more epirubicin-(C 3 -amide)-[anti-HER2/neu] by mechanisms of receptor-mediated-endocytosis.…”

A Metal-containing Nucleoside That Possesses Both Therapeutic and Diagnostic Activity against Cancer

“…Collectively, these results indicate that hENT1 plays a primary role in transporting the metal-containing nucleoside into cells. This is important because the ability of Ir(III)-PPY nucleoside to non-invasively quantify the cellular activity of hENT1 could identify patients that would respond favorably to currently used anti-cancer nucleosides, such as gemcitabine (42,43).…”